Preparation of choline chloride



Patented Dec. 28, 1948 PREPARATION or CHOLINE CHLORIDE OFFICE William F.Gresham, Wilmington, Del., assign or to E. I. du Pont de Nemours &Company, Wilmington, Del., a corporation of Delaware No Drawing.Application May "I, 1946,

- Serial No. 668,019

)laims. 1

This invention relates to the preparation of choline chloride and moreparticularly to a novel synthesis of choline chloride, usingbeta-(alkoxyalkoxy) ethylamines or derivatives thereof as startingmaterials.

Recently low cost processes have been developed for the synthesis ofbeta-(alkoxymethoxy)ethylamines and related compounds such as beta-(alkoxymethoxy) ethyl dimethylamines. These compounds may be prepared inexcellent yield by processes which employ formaldehyde and hydrogencyanide as starting materials. For example, it has been disclosed incopending applications S. N. 430,994, U. S. 2,398,757, and 430,995, U.S. 2,425,628, filed February 14, 1942, that beta- (alkoxymethoxy)ethylamines can be obtained by .reacting formals with formaldehydecyanhydrin and hydrogenating the resulting product. Beta-(alkoxymethoxy)ethyl dimethylamines can be prepared in excellent yieldby hydrogenating beta-(alkoxymethoxy)ethylamlnes in the presence offormaldehyde, suitably with a cobaltcontaining catalyst at a temperatureof about 110 to 120 C. under pressure of about 200 atmospheres (cf.applications S. N. 545,003 filed July 14, 1944, and S. N. 548,802 filedAugust 9, 1944, both now abandoned.

Choline (beta-hydroxethyl trimethylamine hydrate) is a member of thevitamin B group and is generally considered to be necessary for normalnutrition. For example, choline has been found to be essential for eggProduction in chickens (The Biological Action of the Vitamins, Evans,University of Chicago Press, 1942, page 169 et. seq). Synthetic cholinegenerally has been employed in the form of choline chloride.

Heretofore choline chloride has been prepared by the reaction betweenethylene chlorohydrih and trimethylamine under anhydrous conditions(Journal of American Chemical Society, 32, 129 (1910) While it waspossible to prepare choline chloride from anhydrous ethylenechlorohydrin and anhydrous trimethylamine in excellent yield, theprocess, nevertheless, was quite costly in view ofthe relatively highcost of the anhydrous reactants.

An object of this invention is to prepare choline chloride in high yieldfrom relatively inexpensive starting materials. Other objects of theinvention will appear hereinafter.

These objects are accomplished in accordance with the invention bybringing a beta-'(alkoxyalkoxy) ethyl trimethylammonium formate, andmore particularly a beta-(alkoxymethoxy) ethyl 2 trimethylammoniumformate, into contact with hydrochloric acid, (aqueous or anhydrous) andan alkanol, whereby a mixture containing choline chloride is produced.Choline chloride may be separated from the resulting mixture by suitablemethods, such as by removal of the volatile ingredients by distillation.In a specific embodiment the invention contemplates reacting beta-(alkoxymethoxy)ethyl trimethylammonium formate with hydrochloric acidand ethanol, and thereafter separating choline chloride from theresulting reaction product. In another embodiment the inventioncontemplates heating methyl formate with a beta-(alkoxymethoxy) ethyldimethylamine in a closed vessel under superatmospheric pressure,separating beta-(alkoxymethoxy) ethyl trimethylammonium formate fromresulting mixture, treating the said beta- (alkoxymethoxy)ethyltrimethylammonium formate with hydrochloric acid and an alcohol andthereafter separating choline chloride from the resulting reactionproduct. v

The reactions which are involved in the preparation of choline chloridemay be illustrated, in specific embodiments, 'as follows:

The reaction between the beta-(alkoxymethaccordance with Equation 1 isgenerally conducted in a closed vessel at a temperature of about to 2000., preferably to C. It is usually desirable to employ at least a slightexcess of methyl formate and to recover the same after the reactionceases, together with any unreacted beta-(alkoxymethoxy) ethyldimethylamine. The reaction between the beta-(alkoxymethoxy) ethyltrimethylammonium formate, vHCl, and alkanol in accordance with Equation2 takes place quite readily and choline chloride is produced thereby inexcellent yield. This reaction takes place at a convenient rate attemperatures of at least about 50 0., usually about 50 to 0.; highertemperatures may be employed but are generally not necessary.

The invention is illustrated further by means of the following example.

Example 1.A reaction mixture containing beta-(ethoxymethoxy) ethyldimethylamine with an excess of methyl formate was heated in a closedvessel at a temperature of 140 to 150 C. under a pressure of 250 poundsper square inch for several hours. The excess methyl formate wasrecovered by distillation, after which the unconverted tertiary aminewas separated by distillation at 4 mm. pressure. leaving as a residue anonvolatile quaternary formate, (ethoxymethoxy) ethyl trlmethylammoniumformate, having the formula CzHsOCHzOCHzCI-IzN (CH3) :OQCH

This residue of quaternary formate was heated with ethanol and hydrogenchloride in the moial ratio of 1:4:1.5 under refluxing conditions, whilean ethylalethanol azeotrope was removed therefrom by distillation. Whenthe reaction was complete the remaining volatile constituents of thereaction mixture were removed by distillation under reduced pressureleaving a residue of crude choline chloride which was purified bycrystallization from isobutanol.

It is to be understood that the foregoing example is illustrative onlyand that the invention is not limited thereto. If desired, the dialkylformal obtained in accordance with Equation 2 (vide supra) may berecycled to a reactor in which beta-(ethoxymethoxy) ethyl dimethylamineis prepared from the said formal and formaldehyde cyanhydrin. Moreover,the beta-(alkoxymethoxy) ethyl dimethylamine may be beta-(methoxymethoxy) ethyl dimethylamine, in which instance the alkylformate produced in accordance with Equation 2 is methyl formate, whichcan be recycled with beta-(methoxymethoxyl ethyl dimethylamine for thepreparation of quaternary formate in accordance with Equation 1.

Since many diiferent embodiments of the invention may be made withoutdeparting from the spirit and scope thereof it is to be understood thatI do not limit myself except as set forth in the following claims.

I claim:

1. In a process for the synthesis of choline chloride the step whichcomprises contacting a beta- (alkoxyalkoxy) ethyl trimethylammoniumformate with hydrochloric acid and an alkanol, whereby a mixturecontaining choline chloride is produced.

2. A process for the synthesis of choline chloride which comprisesreacting a beta-(alkoxymethoxy) ethyl trimethylammonium formate withhydrochloric acid and an alkanol, and thereafter separating cholinechloride from the resulting reaction products.

3. A process for the synthesis of choline chloride which comprisesreacting a beta-(alkoxymethoxy) ethyl trimethylammonium formate withhydrochloric acid and an alkanol, at a temperature of at least about 50C. and thereafter separating choline chloride from the resultantreaction products.

4. A process for the synthesis of choline chloride which comprisesreacting beta-(ethoxymethoxyoxy) ethyl trimethylammonium formate withhydrochloric acid and ethanol at a temperature of at least about 50 C.and the eafter separating choline chloride from the resultant reactionproducts.

5. A process for the synthesis of choline chloride which comprisesheating methyl formate with a beta-(alkoxymethoxy)ethyi dimethylamine ina closed vessel at a temperature of about to 200 C., separatingbeta-(alkoxymethoxy)ethyl trimethylammonium' formate from the resultingmixture, treating the said beta- (alkoxymethoxy) ethyl trimethylammoniumformate with hydrochloric acid and an alkanol at a temperature of atleast about50 C. and thereafter separating choline chloride from theresultant reaction products. a

6. A process for the synthesis of choline chloride which comprisesheating methyl f ormate with beta-(ethoxymethoxy)ethyl dimethylamine ata temperature of about to C. under superatmospheric pressure, thereafterseparating beta- (ethoxymethoxy)ethyl trimethyiammonium formate from theresulting mixture, treating the said beta- (ethoxymethoxy) ethyltrimethylammonium formate with hydrochloric acid and ethanol at atemperature of at least about 50 C. and thereafter separating cholinechloride from the resultant reaction products.

7. A compound having the formula CzHsOCI-IzOCHzCI-IzN (CH3) sOOCHWILLIAM F. GRESHAM.

REFERENCES CITED The following references are of record in the file oithis patent:

UNITED STATES PATENTS Name Date Loder Feb. 19, 1946 OTHER REFERENCESNumber 5 6 Certificate of Correction Patent No. 2,457,226. December 28,1948.

WILLIAM F. GRESHAM It is hereby certified that errors appear in theprinted specification of the above numbered patent requiring correctionas follows:

Column 1, line 27, after the word abandoned and before the period inserta closing parenthesis; column 3, line 53, claim 2, for the wordresulting read resultant;

column 4, lines 9 and 10, claim 4, for beta-(ethoxymethoxyoxy) readbeta-(ethoxymethozy);

and that the said Letters Patent should be read with these correctionstherein that the same may conform to the record of the case in thePatent Office.

Signed and sealed this 10th day of May, A. D. 1949.

THOMAS F. MURPHY,

Assistant Gammz'ssioner of Patents.

